Studies look at interactions between new hepatitis C drugs and HIV antiretrovirals

Drug-drug interactions between direct-acting antiviral agents for hepatitis C and some antiretroviral medications used to treat HIV are common, but are often modest and can be managed with dose adjustments when treating people with HIV/HCV coinfection, researchers reported at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

Approximately one-third of HIV-positive people are coinfected with hepatitis C virus (HCV). Last year's approval of the first direct-acting antivirals (DAAs) for hepatitis C has ushered in a new era of treatment, but these new drugs are not yet approved for coinfected patients, a group that urgently needs better treatment options.

One factor that slows down development of therapies for the coinfected population is concern about drug-drug interactions. Some drugs can raise or lower concentrations of other medications, leading to elevated levels that can cause worse side-effects or reduced levels that can allow viral breakthrough and treatment failure. Ideally, drug interactions should be assessed in laboratory studies and healthy volunteers before new drugs are tested in coinfected patients, but this does not always happen.

Boceprevir

Ellen Hulskotte from Merck and colleagues presented a poster looking at drug-drug interactions between the HCV protease inhibitor boceprevir (Victrelis) – one of the first two approved hepatitis C DAAs – and the widely used ritonavir-boosted HIV protease inhibitors atazanavir (Reyataz), darunavir (Prezista) and lopinavir/ritonavir (Kaletra).

In this study 39 healthy adult volunteers with neither HCV nor HIV first received 800mg three-times-daily boceprevir for six days. They then took 300/100mg once-daily atazanavir/ritonavir, 600/100mg twice-daily darunavir or 400/100mg twice-daily lopinavir/ritonavir for about two weeks, adding boceprevir during the last five days.

Co-administration of boceprevir with the boosted HIV protease inhibitor was generally well-tolerated with no serious adverse events, but the researchers saw some significant changes in blood drug levels.

Total, maximum and minimum (trough) concentrations of all three HIV protease inhibitors fell, with decreases ranging from about 25% to about 60%. Average total exposure (known as AUC) of atazanavir decreased by 35%, darunavir by 44% and lopinavir by 34%. Boceprevir also decreased ritonavir exposure in all three combinations.

Co-administration with atazanavir/ritonavir did not significantly alter total boceprevir levels. However, lopinavir/ritonavir decreased the total concentration of boceprevir by 45% and darunavir/ritonavir did so by 32%.

These drug-drug interactions had already come to light in February when Merck issued a Dear Health Care Professional letter describing the findings and stating that the company "does not recommend" co-administration of boceprevir with ritonavir-boosted HIV protease inhibitors.

However, as described in another presentation at CROI, boceprevir combined with pegylated interferon and ribavirin appeared safe and effective for HIV/HCV coinfected people taking boosted HIV protease inhibitors. A small number of participants experienced HIV viral breakthrough – which could be a consequence of reduced antiretroviral drug levels – but this occurred in both the boceprevir arm (three of 64 patients) and the group receiving pegylated interferon/ribavirin alone (four of 34 patients).

These conflicting results make it difficult to know how to manage HIV/HCV-coinfected patients today. At a CROI symposium on this topic Jürgen Rockstroh from University of Bonn said, "For now the only recommendation we can give is that patients not newly start boceprevir-based therapy with any of the listed HIV protease inhibitors." However, Douglas Dieterich from Mt Sinai Medical Center suggested in an interview that "it's perfectly appropriate to use either boceprevir or telaprevir as long as you're cognisant of drug-drug interactions" and frequently monitor both HIV and HCV viral load.

Another option, favoured by both Rockstroh and Dieterich, would be to use boceprevir with the HIV integrase inhibitor raltegravir (Isentress).

In another poster at CROI, Clara de Kanter and colleagues from University of Nijmegen in the Netherlands reported findings from a drug-drug interaction study of 24 healthy volunteers who either received 800mg three-times-daily boceprevir for ten days then added 400mg raltegravir once-daily, or else took the same drugs in the reverse order.

No interactions were expected based on how the drugs are processed in the body and concentrations of raltegravir fell within normal range, leading the researchers to conclude that boceprevir has "no clinically meaningful effect" on raltegravir pharmacokinetics.

"Due to the absence of a clinically significant drug interaction," they continued, "raltegravir can be recommended for combined HIV/HCV treatment including boceprevir."

TMC435

In a related study presented during an oral session on breakthroughs in hepatitis, Sivi Ouwerkerk-Mahadevan from Janssen present drug-drug interaction findings for Janssen/Tibotec/Medivir's next-generation HCV protease inhibitor TMC435.

Researchers performed two open-label cross-over studies of healthy volunteers to investigate pharmacokinetic interactions between TMC435 and the antiretrovirals rilpivirine (Edurant), tenofovir (Viread), efavirenz (Sustiva or Stocrin) and raltegravir.

A totally of 48 adult volunteers without HIV or HCV were randomly assigned to receive 150mg TMC435 once-daily, followed by an antiretroviral alone (25mg rilpivirine once-daily, 300mg tenofovir once-daily, 600mg efavirenz once-daily or 400mg raltegravir twice-daily), followed by TMC435 combined with an antiretroviral. Dosing periods ranged from seven to 14 days.

All drug combinations were well-tolerated with no serious adverse events or discontinuations for this reason.

Plasma concentrations of rilpivirine, tenofovir, efavirenz and raltegravir did not change significantly when co-administered with TMC435. Similarly, TMC435 levels did not change appreciably when combined with rilpivirine, tenofovir or raltegravir. Co-administration with efavirenz, however, reduced total TMC435 concentration by about 70%.

The researchers concluded that no dose adjustments are required when combining TMC435 with rilpivirine, raltegravir or tenofovir, but co-administration of TMC435 and efavirenz is not recommended.

"If efficacy and safety are confirmed," they suggested, "these combinations may provide convenient treatment options for HCV/HIV-coinfected patients."

Daclatasvir

Finally, in another poster presentation, Marc Bifano from Bristol-Myers Squibb conducted pharmacokinetic studies in healthy volunteers to look for drug-drug interactions between the investigational HCV NS5A inhibitor daclatasvir (BMS-790052) and antiretrovirals from three classes.

In two studies, a total of 29 participants first received 60mg daclatasvir once-daily for four days, then added either 300/100 atazanavir/ritonavir once-daily or 600mg efavirenz once-daily for up to 18 days. In the third study, 20 participants took the same dose of daclatasvir or 300mg tenofovir once-daily or both for seven days in a cross-over design.

Daclatasvir was generally well-tolerated when combined with all three antiretroviral drugs and no serious adverse events occurred in any of the studies.

Atazanavir/ritonavir and efavirenz plasma concentrations did not change significantly when co-administered with daclatasvir. Daclatasvir total exposure was 110% higher and maximum concentration was 35% higher when given with atazanavir/ritonavir. Levels were reduced by 32% and 67%, respectively when co-administered with efavirenz. Levels of both daclatasvir and tenofovir remained within expected ranges when administered together.

The researchers concluded that "no clinically relevant drug-drug interactions" occurred between daclatasvir and tenofovir, and daclatasvir "did not appear to have any clinically significant effects" on efavirenz or atazanavir/ritonavir.

However, daclatasvir levels were altered when co-administered with atazanavir/ritonavir or efavirenz. The researchers calculated that lowering the daclatasvir dose to 30mg once-daily when given with atazanavir/ritonavir, or raising it to 90mg once-daily when used with efavirenz, "are expected to provide daclatasvir exposure similar to that for 60 mg daclatasvir administered alone."

Taken together, these findings suggest that most HIV/HCV coinfected people should be able to find an antiretroviral therapy regimen that can be safely and effectively used with new hepatitis C drugs.

However, they also show that clinically important drug-drug interactions do occur with some specific combinations, and underscore the demand from community advocates that pharmaceutical companies must perform drug-drug interaction studies in the laboratory and in healthy volunteers before moving into clinical trials of coinfected patients.